HIGD-Driven Regulation of Cytochrome c Oxidase Biogenesis and Function

Timón‐Gómez, Alba; Bartley-Dier, Emma L.; Fontanesi, Flavia; Barrientos, Antoni

doi:10.3390/cells9122620

Cited by 27 publications

(20 citation statements)

References 85 publications

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“…COX4-2 is preferentially expressed under hypoxia and oxidative stress, and it is suggested that the isoform switch results in a more efficient COX activity. [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency

Douiev

Miller

Ruppo

et al. 2021

Cells

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Cytochrome-c-oxidase (COX) subunit 4 (COX4) plays important roles in the function, assembly and regulation of COX (mitochondrial respiratory complex 4), the terminal electron acceptor of the oxidative phosphorylation (OXPHOS) system. The principal COX4 isoform, COX4-1, is expressed in all tissues, whereas COX4-2 is mainly expressed in the lungs, or under hypoxia and other stress conditions. We have previously described a patient with a COX4-1 defect with a relatively mild presentation compared to other primary COX deficiencies, and hypothesized that this could be the result of a compensatory upregulation of COX4-2. To this end, COX4-1 was downregulated by shRNAs in human foreskin fibroblasts (HFF) and compared to the patient’s cells. COX4-1, COX4-2 and HIF-1α were detected by immunocytochemistry. The mRNA transcripts of both COX4 isoforms and HIF-1 target genes were quantified by RT-qPCR. COX activity and OXPHOS function were measured by enzymatic and oxygen consumption assays, respectively. Pathways were analyzed by CEL-Seq2 and by RT-qPCR. We demonstrated elevated COX4-2 levels in the COX4-1-deficient cells, with a concomitant HIF-1α stabilization, nuclear localization and upregulation of the hypoxia and glycolysis pathways. We suggest that COX4-2 and HIF-1α are upregulated also in normoxia as a compensatory mechanism in COX4-1 deficiency.

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“…COX4-2 is preferentially expressed under hypoxia and oxidative stress, and it is suggested that the isoform switch results in a more efficient COX activity. [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency

Douiev

Miller

Ruppo

et al. 2021

Cells

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“…Furthermore, HIGD-1A was required for optimal fusion of mitochondria in DRP1-silenced cells, whereas HIGD-1B silencing did not alter DRP1 expression levels. This may be due to different functions of the HIGD family in different cell lines (37). Hypoxia is one of the important hallmarks of tumor microenvironment (38).…”

Section: Discussionmentioning

confidence: 99%

HIGD‑1B inhibits hypoxia‑induced mitochondrial fragmentation by regulating OPA1 cleavage in cardiomyocytes

et al. 2021

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The dynamic regulation of mitochondrial morphology is key for eukaryotic cells to manage physiological challenges. Therefore, it is important to understand the molecular basis of mitochondrial dynamic regulation. The aim of the present study was to explore the role of HIG1 hypoxia inducible domain family member 1B (HIGD-1B) in hypoxia-induced mitochondrial fragmentation. Protein expression was determined via western blotting. Immunofluorescence assays were performed to detect the subcellular location of HIGD-1B. Cell Counting Kit-8 assays and flow cytometry were carried out to measure cell viability and apoptosis, respectively. Protein interactions were evaluated by co-immunoprecipitation. In the present study, it was found that HIGD-1B serves a role in cell survival by maintaining the integrity of the mitochondria under hypoxic conditions. Knockdown of HIGD-1B promoted mitochondrial fragmentation, while overexpression of HIGD-1B increased survival by preventing activation of caspase-3 and -9. HIGD-1B expression was associated with cell viability and apoptosis in cardiomyocytes. Furthermore, HIGD-1B delayed the cleavage process of optic atrophy 1 (OPA1) and stabilized mitochondrial morphology by interacting with OPA1. Collectively, the results from the present study identified a role for HIGD-1B as an inhibitor of the mitochondrial fission in cardiomyocytes.

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“…There is growing appreciation that CIV contains subunits that are tissue-specific and/or regulated by development, physiological changes (hypoxia and low glucose), and diseases (cancer, ischemia/reperfusion injury, and sepsis) ( 6, 10 ). In addition to the CB, HIGD1C is expressed in kidney proximal tubules ( 16 ) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Higd1c is a novel member of the HIG1 hypoxia inducible domain gene family that also includes Higd1a , Higd1b , and Higd2a . Higd1a and Higd2a , the mammalian orthologs of the yeast respiratory supercomplex factors 1 and 2 ( Rcf1 and Rcf2 ), encode mitochondrial proteins that promote the biogenesis of ETC complexes and their assembly into supercomplexes ( 10 ). To determine the subcellular localization of HIGD1C, we overexpressed FLAG-tagged HIGD1C in HEK293T cells and observed that it co-localizes with the mitochondrial marker HSP60, suggesting that HIGD1C is targeted to mitochondria like HIGD1A and HIGD2A (Fig.…”

Section: Higd1c Is a Novel Mitochondrial Protein Expressed In Cb Glomus Cellsmentioning

confidence: 99%

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

Timón‐Gómez

Scharr

Wong

et al. 2021

Preprint

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The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metabolic syndrome. Upon acute hypoxia (PO2=100 mmHg to <80 mmHg), K+ channels on CB glomus cells are inhibited, causing membrane depolarization to trigger Ca+2 influx and neurotransmitter release that stimulates afferent nerves. A longstanding model proposes that the CB senses hypoxia through atypical mitochondrial electron transport chain (ETC) metabolism that is more sensitive to decreases in oxygen than other tissues. This model is supported by observations that ETC inhibition by pharmacology and gene knockout activates CB sensory activity and that smaller decreases in oxygen concentration inhibit ETC activity in CB cells compared to other cells. Determining the composition of atypical ETC subunits in the CB and their specific activities is essential to delineate molecular mechanisms underlying the mitochondrial hypothesis of oxygen sensing. Here, we identify HIGD1C, a novel hypoxia inducible gene domain factor isoform, as an ETC Complex IV (CIV) protein highly and selectively expressed in glomus cells that mediates acute oxygen sensing by the CB. We demonstrate that HIGD1C negatively regulates oxygen consumption by CIV and acts with the hypoxia-induced CIV subunit COX4I2 to enhance the sensitivity of CIV to hypoxia, constituting an important component of mitochondrial oxygen sensing in the CB. Determining how HIGD1C and other atypical CIV proteins expressed in the CB work together to confer exquisite oxygen sensing to the ETC will help us better understand how tissue- and condition-specific CIV subunits contribute to physiological function and disease and allow us to potentially target these proteins to treat chronic diseases characterized by CB dysfunction.

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HIGD-Driven Regulation of Cytochrome c Oxidase Biogenesis and Function

Cited by 27 publications

References 85 publications

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency

Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency

HIGD‑1B inhibits hypoxia‑induced mitochondrial fragmentation by regulating OPA1 cleavage in cardiomyocytes

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

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